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Chronic lymphocytic leukemia (CLL) and the other low-grade non-Hodgkin lymphomas are among the most common lymphoid malignancies. Recent studies suggest that more than 4% of the general population over age 40 harbor a population of clonal B cells with the phenotype of either CLL or another B-cell malignancy, a condition now designated monoclonal B-cell lymphocytosis (MBL). Although all cases of CLL appear to be preceded by MBL, the majority of individuals with MBL will not develop a hematologic malignancy. The biologic characteristics and clinical implications of MBL appear to differ based on whether it is identified during the diagnostic evaluation of lymphocytosis or incidentally discovered through screening of individuals with normal lymphocyte counts as part of research studies using highly sensitive detection methods. In this paper, we provide a state of the art review on the prevalence, nomenclature, biology, natural history and clinical management of MBL.

Background The transient Headache and Neurological Deficit with cerebrospinal fluid Lymphocytosis (HaNDL) Syndrome is a rare form of primary headache, with few cases reported in children. Case presentation and review We report the case of a 15-year-old female with HaNDL syndrome showing paresthesia to the right side of her face and upper limbs, asthenia, dysarthria and aphasia, followed by left periorbital pulsating headache with moderate nausea, lasting about four hours. Forty-four cases of pediatric HaNDL syndrome are reported in literature (ours included), but only 25 fulfilled all diagnostic criteria according to ICHD-3. Overall, 59.1% were females. Sensory symptoms affected 71.4% of patients, followed by impaired speech (69.0%) and motor symptoms (52.4%). At CSF analysis, the mean value of white blood cells was 201.1/µl; proteinorrhachia was reported in 31 patients (70.5%). When asked, neuroimaging was negative. Symptomatic treatment was reported only in 14 patients (31.8%). Conclusions HaNDL is a rare self-limiting syndrome affecting both adults and children. The etiology is unknown, but autoimmune mechanisms have been proposed. HaNDL is a diagnosis of exclusion: differential diagnoses include stroke, tumors, epilepsia, neuro-infective disorders, autoimmune encephalitis, vasculitis, hemiplegic migraine and migraine with aura. Usually, HaNDL episodes last less than 3 months; therapy is symptomatic. The diagnostic work out includes CSF analysis, neuroimaging and EEG. The treatment is symptomatic, and the course is self-limiting, usually resolving within 3 months.

Our aims were to assess performance of duodenal intraepithelial lymphocyte counting for diagnosis of Helicobacter pylori (H. pylori) gastritis, and effects of eradication therapy on intraepithelial lymphocytosis. Paired duodenal and gastric biopsies from subjects with a pathologic diagnosis of H. pylori gastritis were reviewed. Higher duodenal intraepithelial lymphocyte counts were observed in 40 subjects with H. pylori gastritis (26 ± 5 per villus) than 52 subjects negative for H. pylori (12 ± 2 per villus). After successful eradication therapy, duodenal lymphocytes were indistinguishable from H. pylori–negative subjects, whereas they remained elevated after failed eradication therapy. This study confirms previous reports of increased duodenal intraepithelial lymphocytes in patients with concurrent Helicobacter pylori gastritis. Intraepithelial lymphocyte counts of > 15 per villus or > 10 per 100 enterocytes were predictive of infection. Duodenal lymphocytosis decreases significantly after successful eradication therapy but remains elevated when treatment fails.

Monoclonal B-cell lymphocytosis (MBL) is a precursor to CLL. Other than age, sex, and CLL family-history, little is known about factors associated with MBL risk. A polygenic-risk-score (PRS) of 41 CLL-susceptibility variants has been found to be associated with CLL risk among individuals of European-ancestry(EA). Here, we evaluate these variants, the PRS, and environmental factors for MBL risk. We also evaluate these variants and the CLL-PRS among African-American (AA) and EA-CLL cases and controls. Our study included 560 EA MBLs, 869 CLLs (696 EA/173 AA), and 2866 controls (2631 EA/235 AA). We used logistic regression, adjusting for age and sex, to estimate odds ratios (OR) and 95% confidence intervals within each race. We found significant associations with MBL risk among 21 of 41 variants and with the CLL-PRS (OR = 1.86, P = 1.9 × 10−29, c-statistic = 0.72). Little evidence of any association between MBL risk and environmental factors was observed. We observed significant associations of the CLL-PRS with EA-CLL risk (OR = 2.53, P = 4.0 × 10−63, c-statistic = 0.77) and AA-CLL risk (OR = 1.76, P = 5.1 × 10−5, c-statistic = 0.62). Inherited genetic factors and not environmental are associated with MBL risk. In particular, the CLL-PRS is a strong predictor for both risk of MBL and EA-CLL, but less so for AA-CLL supporting the need for further work in this population.

PurposePeripheral blood T lymphocytosis (PBTL) is a rare, yet poorly understood manifestations of thymoma, which is postulated to be linked with autoimmune/paraneoplastic manifestations such as myasthenia gravis (MG), pure red cell aplasia (PRCA), etc.; more commonly encountered in this neoplasm.MethodWe aim to describe the flowcytometric immunophenotypic data of PBTL in a 43-year-old male; 6 months after successful completion of chemoradiotherapy (CT/RT) for a large, invasive, and metastatic type B1 thymoma; and present a comprehensive review of all such cases reported over last 42 years (N = 21) (1977–2019).ResultA larger size of the tumors (≥ 10 cm), presence of local invasion and/or distant metastasis, and type B (cortical or lymphocyte rich) histology were more likely to be associated with PBTL. Tumors associated with MG/PRCA (N = 9/21) tend to have lower PBTL compared to those without such manifestations; and PBTL subsided following thymectomy with or without CT/RT. Immunophenotypic analysis of PB revealed a CD8 +  > CD4 + mature (naïve) polyclonal T cells resembling late cortical thymocytes.ConclusionThymic intratumoral microenvironment might influence occurrence PBTL that may have a pathophysiologic link to development of autoimmune manifestations. Immunophenotypic characteristics of peripheral blood lymphoid cells should be the clue for accurate characterization and to avoid a misdiagnosis of a lymphoproliferative neoplasm.

Purpose Activating germline mutations in CARD11 have recently been linked to a rare genetic disorder associated with congenital B cell lymphocytosis. We describe a patient with a similar clinical phenotype who had a de novo germline G123D CARD11 mutation. Methods Whole exome sequencing was performed on DNA from the patient and his biological parents. Laboratory studies examined characteristics of the patient’s B and T lymphocytes. A CARD11 cDNA containing the mutation was transfected into a lymphocyte cell line to gain an understanding of its function. RNA sequencing was performed on samples from the patient and from patients with alternate germline CARD11 mutations and differential gene expression analysis was performed. Results The patient had a decade-long history of severe polyclonal B lymphocytosis in the 20,000–90,000 lymphocytes/mm 3 range, which was markedly exacerbated by EBV infection and splenectomy at different times. He had a heterozygous germline CARD11 mutation causing a G123D amino acid substitution, which was demonstrated to induce NF-κB activation in unstimulated lymphocytes. In contrast to previous patients with CARD11 mutations, this patient’s B cells exhibited higher expression of several cell cycle progression genes, as well as enhanced proliferation and improved survival following B cell receptor stimulation. Conclusions This is the third reported germline and first de novo CARD11 mutation shown to cause congenital B cell lymphocytosis. The mutation was associated with a dramatically greater lymphocytosis than in previously described cases, disproportionate to the level of constitutive NF-κB activation. However, comparative review of the patient’s clinical history, combined with additional genomic and functional analyses, underscore other important variables that may affect pathophysiology or regulate mutant CARD11 function in B cell proliferation and disease. We now refer to these patients as having BENTA disease ( B cell E xpansion with N F-κB and T cell A nergy).

Although the risk of progression from monoclonal B-cell lymphocytosis (MBL) to chronic lymphocytic leukemia (CLL) has been well characterized, it is unknown whether other common complications associated with CLL, such as increased risk of infection, occurs in individuals with MBL. We used the Mayo CLL database to identify cohorts of individuals with newly diagnosed MBL ( n =154) or newly diagnosed CLL ( n =174) who resided within 50 miles of Mayo Clinic. A cohort of 689 adult patients seen for a general medical examination who resided within 50 miles of Mayo clinic and who enrolled in a case–control study of non-Hodgkin lymphoma (NHL) was used as a comparison cohort. Hospitalization with infection was more common among individuals with MBL (25/154; 16.2%), and CLL (32/174; 18.4%) than controls (18/689; 2.6%). On pooled multivariable Cox proportional hazards analysis of all 1017 patients (controls, MBL and CLL), male sex (hazards ratio (HR)=2.3; P =0.002), major co-morbid health problems (HR=1.7, P =0.04), the presence of CLL (HR=3.2, P <0.001), treatment for progressive CLL (HR=2.4, P =0.001) and the presence of MBL (HR=3.0, P =0.001) were independently associated with risk of hospitalization for infection. These results suggest the risk of serious infection in clinical MBL is substantially greater than the risk of progression requiring treatment.